Examination shows how a protein prevents cells from assaulting their own DNA

Overview

• Post By : Kumar Jeetendra


• Source: Ecole Polytechnique Fédérale de Lausanne


• Date: 20 Aug,2020

Viruses multiply by injecting their DNA into a host cell. Once it passes the intracellular fluid, then this foreign substance triggers a defense mechanism referred to as the cGAS-STING pathway. This, in turn, binds to another protein named Stimulator of Interferon Genes (STING), which induces an inflammatory immune reaction.

From time to time, the material contained within the fluid – and also connected with the cGAS protein – comes not out of a virus but from the cell itself, for example after the nucleus has inadvertently ruptured. While this happens, the cGAS-STING pathway is not activated. Researchers at EPFL have shown how cells can respond differently to their own DNA and also to genetic material from a pathogen – and prevent attacking the wrong target. Their discovery, published in a paper in the journal Science, sheds new light on the complex processes at work in the human body’s inflammatory response.

The group, headed by Prof. Andrea Ablasser and working together with colleagues from the labs of Prof. Conquer Fierz and Prof. Selman Sakar, found new insights to the key job of a small protein known as Barrier-to-Autointegration Factor (BAF). They revealed that, by binding to the inoffensive DNA, BAF prevents the cGAS protein by doing the same, thereby stopping the cGAS-STING pathway in its paths.

BAF reinforces the cell nucleus, linking the nuclear envelope (or membrane) into the DNA inside. Experiments have demonstrated that if this protein is removed from lab-grown cells, the nucleus ruptures. This violation releases the genetic material to the intracellular fluid, in which it comes into contact with the cGAS protein and activates the cGAS-STING pathway – exactly as if it were foreign DNA.

We can therefore conclude that BAF plays a key role in preventing the cell from attacking its own DNA.”

Baptiste Guey, one of the paper’s lead authors

There are various approaches to create a nucleus to rupture, like by applying mechanical strain. However, based on Baptiste Guey, among the paper’s lead writers, only one of those methods – eliminating the BAF protein – based causes an immune response.

The protein’s inhibitor function is extremely important: although the cGAS-STING pathway enables the body fight off infections, in addition, it should be kept in check. “Nuclei do occasionally rupture, but cells are able to repair the damage,” says Marilena Wischnewski, yet another lead author of this paper. “If cGAS jumped to the DNA every time that occurred, the consequences would be more serious.”

The hazards of an overactive cGAS-STING pathway can be seen in Aicardi-Goutières syndrome: a rare and usually fatal hereditary disorder which causes an excessive inflammatory reaction as though the body’s cells were under continuous assault from invading pathogens.

BAF is also believed to play a role in some kinds of tumor. Based on Wischnewski, a high concentration of the protein in cancer cells might be associated with a poorer prognosis. “It might be that BAF makes tumors more resistant,” she clarifies. “By preventing activation of the cGAS-STING pathway, it may enable cancer cells to evade the body’s immune system.”

The protein is found in varying quantities in various kinds of cells. The group is planning to dig deeper into those variations as they seek to know how distinct tissue types respond to infection and inflammation.